This is the second submission of this Conte Center for the Neuroscience of Mental Disorders (CCNMD) entitled "The Neurobiology of Dopamine in Schizophrenia. Schizophrenia might result from neurodevelopmental disruptions involving multiple cortico-subcortical and intracortical networks. While the precise mapping of these alterations remains unclear, multiple lines of evidence suggest that prefrontal cortex (PFC) is critically involved in the neurocircuitry underlying the pathophysiology of schizophrenia. Within these circuits, dysregulations of DA (DA) and glutamate (GLU) transmission have been strongly implicated. The unifying hypothesis of the Center is that schizophrenia is associated with an imbalance of DA (DA) systems, characterized by a persistent deficit in prefrontal cortical DA function (contributing to the cognitive impairment observed in these patients) and an intermittent excess of subcortical DA function (contributing to the emergence of psychotic states). This DA imbalance might stem from altered PFC connectivity involving GLU transmission and from a failure of PFC to appropriately modulate DA function. The overall goal of the Center is to combine clinical imaging with Positron Emission Tomography (PET) and epigenetic and transgenic animal models in mice and rhesus monkeys to test this hypothesis. A set of interrelated clinical and preclinical investigations are proposed to 1) better characterize the existence of such a DA imbalance in schizophrenia; 2) explore the underlying biological mechanisms that might account for such a DA phenotype; 3) understand the consequence of this imbalance for brain functions, clinical symptoms and treatment. Six highly integrated projects are proposed, including two clinical imaging projects in patients with schizophrenia (Projects by Abi-Dargham and Laruelle) four preclinical projects, performed in rhesus monkeys (Projects by Haber and Javitt) and mice (Projects by Kandel and Rayport). These projects will investigate this single hypothesis with state-of-the art methodologies. Six cores will provide shared resources and support for these projects (Administrative, Biostatistics and Data management, Clinical, Brain Imaging, Molecular and Cellular, and Neurochemistry Cores). Prominent investigators from three Institutions (Columbia University, University of Rochester and Nathan Kline Research Institute) will bring specific research skills and collaborate closely in this translational investigation. By integrating basic and clinical research in a unique way, this Center will provide a fundamental advance in understanding the neural substrates underlying schizophrenia, the developmental etiology of this phenotype, and the implications of these findings for the development of new treatment modalities.